Toripalimab in combination with chemotherapy effectively suppresses local recurrence and metastatic sarcomatoid renal cell carcinoma: A case report

Abstract

BACKGROUND

Sarcomatoid renal cell carcinoma (SRCC) is a rare variant of renal cell carcinoma associated with an unfavorable prognosis. The efficacy of conventional chemotherapy and targeted therapies are limited, whereas the emergence of immune checkpoint inhibitor has introduced new avenues for managing advanced SRCC.

CASE SUMMARY

A 77-year-old female patient was referred to our hospital following the incidental detection of a right kidney tumor without specific symptoms. The tumor was successfully resected, and subsequent pathological examination confirmed SRCC. She experienced both local recurrence and distant metastasis eight months after the initial laparoscopic resection. Following six cycles of toripalimab combined with pirarubicin chemotherapy, the patient achieved a partial response. Subsequently, the patient attained an almost-complete continuous response to toripalimab monotherapy maintenance for an additional six cycles. She has not experienced disease progression for 15 months, and her overall survival has reached 24 months thus far.

CONCLUSION

Combination therapy with programmed death 1 antibodies and cytotoxic agents may be a recommended first-line treatment approach for SRCC.

Key Words: Renal cell carcinoma; Sarcomatoid dedifferentiation; Immune checkpoint inhibitor; Chemotherapy; Case report

Core Tip: Sarcomatoid renal cell carcinoma (SRCC) is a highly aggressive and uncommon malignant tumor of the kidney, which is associated with a rapid clinical course and unfavorable prognosis compared to conventional RCC. Traditional chemotherapy and targeted therapies have limited efficacy against SRCC. We present a rare case of recurrent and metastatic SRCC that achieved excellent outcomes with the combination of immunotherapy and chemotherapy. This report sheds new light on diagnostic and therapeutic approaches for SRCC.

INTRODUCTION

Sarcomatoid carcinoma is a highly aggressive malignancy characterized by its lack of differentiation and is composed of both epithelial and mesenchymal cells, commonly affecting the female genital system, upper aerodigestive tract, and gastrointestinal tract[1]. It rarely occurs in the urinary system. Sarcomatoid renal cell carcinoma (SRCC) is a distinct type of renal malignant tumor, accounting for approximately 1-8% of renal cell carcinoma[2]. Compared to conventional RCC, SRCC exhibits a higher degree of malignancy and a poorer prognosis, with an increased propensity for infiltration and metastasis[2,3]. Due to its infrequent occurrence in clinical practice, the understanding of this variant is restricted. We here present a case of SRCC managed at our institution in June 2022. To broaden our understanding of this complex disease, we conducted a meticulous review of pertinent domestic and international literature, specifically focusing on the clinical features associated with SRCC.

CASE PRESENTATION

Chief complaints

The patient was diagnosed with SRCC over 8 months ago and had experienced abdominal pain for more than 1 month.

History of present illness

A 77-year-old female patient was found to have a tumor in her right kidney during a medical examination in June 2022, which raised concerns about malignancy (Figure 1A). She was subsequently admitted to the urology department of our hospital. After ruling out distant metastases and surgical contraindications, she underwent a laparoscopic right radical nephrectomy under general anesthesia on June 16, 2022. The pathological examination revealed sarcomatoid dedifferentiation, characterized by a mixture of large, abnormal spindle cells with numerous nuclei resembling a tumor. Further examination identified regions mimicking osteosarcoma and areas harboring tubular structures suggestive of sarcomatoid carcinoma. The sarcomatoid component comprised the predominant element, exceeding 80% of the tumor volume. Notably, the tumor remained confined beneath the renal capsule, with no discernible infiltration into the capsule itself, renal pelvis, ureteral margins, or vasculature. The three perihilar lymph nodes exhibited no signs of metastatic spread. Immunohistochemical analysis depicted in Figure 2 revealed the epithelium to be positive for cytokeratin-pan and Pax-8, indicating epithelial lineage. Conversely, CD34 and S-100 demonstrated a lack of immunoreactivity, further refining the diagnosis. Smooth muscle differentiation was focally evident with smooth muscle actin positivity, while desmin expression highlighted scattered myogenic elements. MyoD1 negativity suggested an immature myogenic phenotype. The proliferative index, as assessed by Ki-67, was approximately 50%, with prominent CD68 expression indicative of macrophages. Ecological momentary assessment (EMA) positivity confirmed the epithelial nature, while Vimentin and SATB2 positivity was also observed. Programmed Cell Death Ligand 1 (PD-L1) expression, evaluated using the 22C3 clone, yielded a combined positive score (CPS) of 1. Due to the COVID-19 outbreak, the patient was unable to attend scheduled post-operative follow-up appointments and did not receive additional therapy. She presented to our hospital in February 2023, complaining of abdominal pain for over one month.

Figure 1 Computed tomography scan findings in the patient with sarcomatoid renal cell carcinoma. A and E: The computed tomography (CT) scan revealed a tumor in the right kidney, initially believed to be renal cell carcinoma, before surgery in June 2022; B and F: The cancer recurred in the right renal fossa and metastasized to the liver in February 2023; C and G: After six cycles of toripalimab plus pirarubicin chemotherapy, the CT scan showed a notable decrease in the lesions of the right retroperitoneum and liver, indicating a partial response; D and H: After six cycles of toripalimab maintenance therapy, the CT scan showed significant improvement in the original renal tumor area and liver lesions, indicating almost complete remission.

Figure 2 Pathological examinations in the patient with sarcomatoid renal cell carcinoma. A: 100 ×; B: 200 ×. They displayed a significant proliferation of extremely abnormal spindle cells mixed with tumor giant cells. Additionally, there were areas resembling osteosarcoma and regions with tubular structures. The sarcomatoid component accounts for more than 80% of the tumor; C: The renal cell carcinoma (RCC) component exhibits cytokeratin-pan positivity (400 ×); D: The RCC component was positive for ecological momentary assessment (400 ×); E: Vimentin shows strong immunoreactivity in the sarcomatoid areas and weak immunoreactivity in the renal cell carcinoma areas (400 ×); F: STATB2 exhibits strong immunoreactivity in sarcomatoid areas but not much immunoreactivity in RCC areas (400 ×).

History of past illness

The patient's medical history included long-standing hypertension, which had been managed with nifedipine gastro-resistant tablets (30 mg once daily) to maintain her blood pressure at approximately 140 mmHg/90 mmHg.

Personal and family history

The patient's medical and familial histories were unremarkable.

Physical examination

The abdominal examination revealed light pressure pain in the epigastrium. No other physical abnormalities were observed, and the patient’s Eastern Cooperative Oncology Group performance status was 1.

Laboratory examinations

The results of patient’s routine laboratory tests, including whole blood count, liver and kidney function tests, urine analysis, electrolytes, and thyroid function, were all within normal limits.

Imaging examinations

The computed tomography (CT) scan findings revealed the presence of abnormal tissue in the right renal fossa and psoas muscle, which was indicative of a recurrent SRCC. Additionally, a low-density lesion was observed in the left hepatic lobe, which is suspicious for metastasis disease (Figures 1B and F).

FINAL DIAGNOSIS

Contemplating the aforementioned clinical data and the lack of a history of SRCC, the patient was diagnosed with postoperative SRCC with local recurrence and hepatic metastases.

TREATMENT

From February 2023 to the present, the patient received medical treatment in the Department of Oncology. The treatment involved administering toripalimab at a dose of 240 mg on the first day and pirarubicin at a dose of 50 mg on the first day every 21 days, for a total of six cycles. The treatment was well tolerated without any notable adverse reactions. A follow-up CT scan conducted on June 12, 2023 revealed a significant decrease in the size of the lesions in the right retroperitoneum and liver, indicating a partial response (Figure 1C and G). Subsequently, the patient proceeded with toripalimab 240 mg on day 1 every 21 days for an additional six cycles as part of her maintenance medication. After two treatment cycles, the patient exhibited low FT3 and FT4 levels and high thyrotropin levels, accompanied by fatigue and anorexia. Hypophysitis and adrenal dysfunction were excluded. In the wake of immune checkpoint inhibitor (ICI) therapy, the patient developed iatrogenic hypothyroidism, necessitating levothyroxine replacement therapy. The dosage was titrated based on serial thyroid function assessments.

OUTCOME AND FOLLOW-UP

The serial imaging of CT obtained on December 19, 2023 (Figures 1D and H) demonstrated a dramatic response to treatment, with near complete resolution of the initial renal mass and hepatic lesions, suggestive of a near complete remission. Additionally, thyroid function tests revealed normalization of thyrotropin, free T3, and free T4 levels, with concomitant resolution of clinical symptoms. Notably, the treatment course was well-tolerated, with no significant adverse events documented. The patient remains on active treatment with close clinical monitoring.

DISCUSSION

SRCC is an exceedingly rare malignancy. The dedifferentiated form is represented rather than being considered a distinct histological subgroup of RCC. Sarcomatoid dedifferentiation can be observed in most varieties of RCC[3-5]. The clear cell and chromophobe subtypes are the ones most frequently affected[6,7]. The etiology of the disease remains elusive. Research suggests that the sarcomatoid component and epithelial component in RCC may share a common cellular origin[8]. The epithelial-mesenchymal transition of the tumor cells is believed to be associated with the sarcomatoid transformation[9].

The clinical manifestation of SRCC is characterized by non-specific symptoms such as flank discomfort, abdominal pain, and hematuria, which vary depending on the stage of the disease at the time of diagnosis. Distant metastases commonly occur in the lung, bone, lymph nodes, and liver[2,10]. Currently, there are no reliable imaging techniques that can distinguish between SRCC and non- SRCC. The diagnosis relies on the evaluation of tissues, particularly through the use of immunohistochemistry staining, which is a crucial component. Commonly employed markers encompass cytokeratin-pan, EMA, PAX-8, vimentin, and others.

The management of SRCC closely resembles that of RCC. Surgery is the primary therapeutic option for localized diseases. Earlier studies have indicated that a majority of SRCC patients who underwent nephrectomy experienced disease recurrence within five to 26 months following the surgical procedure[11]. The patient experienced a recurrence of the disease eight months after the operation, which is consistent with the aggressive nature of the disease. For advanced SRCC, the most common treatments are systemic therapies. However, the role and timing of cytoreductive surgery remain controversial. Prior research has shown that anthracycline-based chemotherapy or antiangiogenic agents have limited efficacy, resulting in a 5-year overall survival rate of approximately 23.5%–33%, regardless of the treatment approach[10]. Nevertheless, those with a more prominent sarcomatoid component may derive greater benefits from cytotoxic chemotherapy[12]. Due to the presence of a sarcomatoid component exceeding 80%, we have decided to consider cytotoxic treatment for our patient. Recently, the discovery of ICIs, specifically programmed death 1 (PD-1) /PD-L1 antibodies, has transformed the treatment landscape of RCC and other cancer types. Researchers have ascertained that SRCC tumor cells exhibit augmented levels of PD-L1 and heightened concentrations of PD-1 on tumor-infiltrating lymphocytes compared to non-sarcomatoid RCC[13]. A study encompassing 118 instances of SRCC further elucidated that a mere 8% of the epithelial components within the sarcomatoid regions concomitantly both PD-L1 and PD-1, while 41% of the sarcomatoid areas did[14]. The control group comprised non-sarcomatoid RCC. The findings intimate that immune checkpoint blockade, which has garnered corroborating evidence from an escalating corpus of clinical data, may prove advantageous for individuals afflicted with SRCC. Patients with metastatic RCC devoid of prior treatment were evaluated in the KEYNOTE-426 trial[15]. It appraised the efficacy of pembrolizumab, an anti-PD-1 antibody, in conjunction with axitinib, a VEGFR TKI, and sunitinib in their management. Within the cohort of 105 patients exhibiting sarcomatoid attributes, the objective response rate (ORR) was 58.8% for those who received pembrolizumab alongside axitinib, contrasted with 31.5% for those who received sunitinib. Furthermore, subsequent to the CheckMate 214 trial, additional studies[16,17] have evinced that the combination of ipilimumab and nivolumab facilitated durable benefits for patients with metastatic clear cell RCC and sarcomatoid features. The median progression-free survival spanned 26 and a half months in the combination group, whereas it was merely 5.1 months in the sunitinib group. Burgeoning evidence indicates that ICIs can potentiate outcomes in SRCC.

Toripalimab, a Chinese-developed humanized anti-PD-1 immunoglobulin G4 monoclonal antibody, by impeding the binding of PD-1 to its ligands PD-L1 and PD-L2, potentiates the immune system's capacity to combat cancer[18]. China has sanctioned its utilization for the management of six neoplastic entities, encompassing melanoma[19], urothelial carcinoma[20], esophageal carcinoma[21], NSCLC[22], and others. The United States Food and Drug Administration approved the employment of toripalimab in combination with chemotherapy as the inaugural treatment for advanced or metastatic nasopharyngeal cancer in October 2023[23]. It was evinced at European Society for Medical Oncology 2023 that the combination of toripalimab and axitinib exhibited a markedly superior overall response rate (ORR 56.7% vs sunitinib) and progression-free survival (18 months) over sunitinib when utilized as the primary treatment for advanced RCC[24]. Congruent with these findings, the 2023 edition of the Chinese Society of Clinical Oncology Guidelines advocates toripalimab as the preferred initial treatment for metastatic RCC.

Based on the patient's age, performance status, pathological subtype, and drug availability, we administered a combination of anthracycline-based chemotherapy (pirarubicin) and toripalimab immunotherapy. Upon completing six cycles, she attained a near-complete response as determined by imaging evaluation. She had not experienced disease progression for 15 months, and her overall survival has reached 24 months thus far. PD-L1 expression was not elevated in this case (CPS 1), and the exceptional outcomes are challenging to elucidate. One reason is that test results exhibit heterogeneity, as PD-L1 is unevenly distributed within tumors. Another reason is that PD-L1 expressions do not confer a significant prognostic impact on SRCC. The post hoc analysis of the CheckMate 214 trial revealed that efficacy was superior in patients treated with nivolumab and ipilimumab versus sunitinib, irrespective of tumor PD-L1 expression level[16]. Until now, there is no standard biomarker that can accurately predict the efficacy of immunotherapy. The specific mechanism by which immunotherapy is effective for sarcomatoid cancer warrants further investigation. Previous studies have reported that skin and endocrine adverse events, such as hypothyroidism, hyperthyroidism, hypophysitis, and diabetes, are the principal toxicities of PD-1/PD-L1 antibodies[25]. Among immune-related adverse events, thyroid dysfunction is the most prevalent. However, thyroid dysfunction is generally reported as moderate or asymptomatic, graded one or two on clinical trials; fewer than 1% of cases are graded three or four[26,27]. It is also not essential for patients to discontinue ICIs therapy, as hormone replacement is generally able to restore functional status promptly[28]. The patient experienced grade-2 hypothyroidism, which was successfully managed with thyroid hormone replacement therapy without treatment interruptions.

CONCLUSION

The integration of both cytotoxic agents and PD-1 antibodies warrants exploration as a potential first-line therapeutic strategy for SRCC. However, robust prospective trials are imperative to definitively establish the efficacy of this treatment paradigm.